Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia. Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for microvascular and macrovascular disease, including nephropathy, neuropathy, retinopathy, hypertension, stroke, and heart disease. Therefore, glucose homeostasis is critically important for the treatment of diabetes.
Type I diabetes (IDDM) is associated with a deficiency of insulin. Type II, noninsulin dependent diabetes mellitus (NIDDM) is associated with a resistance to the stimulating or regulatory effect of insulin on glucose and lipid metabolism in the main insulin-sensitive tissues, namely, the muscle, liver and adipose tissue. This resistance to to the effect of insulin results in insufficient activation of glucose uptake, oxidation and storage in muscle, inadequate repression of lipolysis in adipose tissue and inadequate supression of glucose production and secretion in liver.
Standard treatments for NIDDM, which have not changed substantially in years, are all associated with limitations. Physical exercise and reduction in calorie intake improves the diabetic condition; however compliance is generally poor. Increasing the plasma level of insulin, either by administering an oral hypoglycemic such as a sulfonylurea (e.g. tolbutamide or glipizide) or by injecting insulin results in insulin levels which are sufficient to stimulate insulin-resistant tissues. However, low levels of plasma glucose and a heightened level of insulin resistance can result.
Thiazolidinediones (glitazones) were suggested to ameliorate many symptoms of NIDDM. These agents increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of NIDDM, hopefully resulting in normalized levels of plasma glucose, triglycerides and nonesterified free fatty acids. However, serious undesirable effects have been observed, including cardiac hypertrophy, hemodilution and liver toxicity.
Hyperlipidemia is a condition that is characterized by an abnormally high level of serum lipids. This includes cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins. See the Merck Manual, 16th Ed. 1992 (see for example pp. 1039-1040) and xe2x80x9cStructure and Metabolism of Plasma Lipoproteinsxe2x80x9d in Metabolic Basis of Inherited Disease, 6th Ed. 1989, pp. 1129-1138. One form of hyperlipidemia is hypercholesterolemia, which is characterized by elevated LDL cholesterol levels. The initial treatment for hypercholesterolemia is often reduced dietary fat and cholesterol. Coupled with an appropriate exercise regimen, this can be an effective means by which to reduce hyperlipidemia. More typically, this means of lowering hyperlipidemia is insufficient, making drug therapy to reduce serum LDL-cholesterol more appropriate.
Although it is desirable to lower elevated levels of LDL cholesterol, it is also desirable to increase levels of HDL cholesterol, since increased levels of HDL are associated with a reduced risk for coronary heart disease (CHD). See, for example, Gordon, et al., Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N. England J. Med., 325, 373-381 (1991); and Kannel, et al., Ann. Internal Med., 90, 85-91 (1979). An example of an HDL raising agent is nicotinic acid.
It is suggested that thiazolidinedione compounds exert their effects by binding to the peroxisome proliferator activated receptor (PPAR) family of receptors, controlling certain transcription elements having to do with the biological entities listed above. See Hulin et al., Current Pharm. Design (1996) 2, 85-102. Three sub-types of PPARs have been discovered and described: PPARxcex1, PPARxcex3 and PPARxcex4. PPARxcex1 is activated by a number of medium and long-chain fatty acids. It is involved in stimulating xcex2-oxidation of fatty acids. PPARxcex1 is also activated by compounds known as fibric acid derivatives. These fibric acid derivatives, such as clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil reduce plasma triglycerides along with LDL cholesterol, and they are primarily used for the treatment of hypertriglyceridemia.
PPARxcex3 receptor subtypes are involved in adipocyte differentiation. The DNA sequences for the PPARxcex3 receptors are described in Elbrecht, et al., BBRC 224;431-437 (1996). Although peroxisome proliferators, including the fibrates and fatty acids, activate the transcriptional activity of PPARs, only prostaglandin J2 derivatives have been identified as natural ligands of the PPARxcex3 subtype, which also binds to thiazolidinedione antidiabetic agents with high affinity. The glitazones have been shown to bind to the PPARxcex3 subtype.
The human nuclear receptor gene PPARxcex4 (hPPARxcex4) has been cloned from a human osteosarcoma cell cDNA library and is fully described in A. Schmidt et al., Molecular Endocrinology, 6 :1634-1641 (1992), herein incorporated by reference. PPARxcex4 is also referred as PPARxcex2 and NUC1.
The present invention is directed to a compound represented by formula I or Ia: 
or a pharmaceutically acceptable salt thereof, wherein:
A is optionally a single or double bonded carbon or a single or double bond;
R1 is selected from a group consisting of: H, C1-5 alkyl, C2-15 alkenyl, C2-15 alkynyl and C3-10 cycloalkyl, said alkyl, alkenyl, alkynyl, and cycloalkyl optionally substituted with 1 to 3 groups of Ra;
R2 is selected from a group consisting of: H, C1-15 alkyl, C2-15 alkenyl, OR3, CO2alkyl, COalkyl, OH, xe2x80x94OC(O)R3, C2-15 alkynyl, C5-10 aryl, C5-10 heteroaryl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of Ra;
R3 is selected from a group consisting of: H, NHR1, NHacyl, C1-15 alkyl, C2-15 alkenyl, C1-15 alkoxy, CO2alkyl, OH, C2-15 alkynyl, C5-10 aryl, C5-10 heteroaryl said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of Ra;
R4 is selected from the group consisting of: R2, xe2x80x94Dxe2x80x94R5 or 
R5 is selected from the group consisting of: C5-10 aryl and C5-10 heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 groups of Ra; 
R8 is selected from the group consisting of CR6R7, O, NR6, and S(O)P;
R6and R7 are independently selected from the group consisting of H, C1-6 alkyl;
B is a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 0 to 3 heteroatoms selected from the group consisting of O, S and N, the heteroatom being substituted at any position on the five or six membered heterocycle, the heterocycle being optionally unsubstituted or substituted with 1 to 3 groups of Ra;
D is selected from the group consisting of: O, S(O)p and NR1;
X1 and X2 are independently selected from a group consisting of: H, OH, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, halo, OR3, C5-10 aryl, C5-10 aralkyl, C5-10 heteroaryl and C1-10 acyl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 groups of Ra;
Ra represents a member selected from the group consisting of: halo, aryl, heteroaryl, CF3, OCF3, xe2x80x94Oxe2x80x94, CN, NO2, R3, OR3; SR3, S(O)R3, SO2R3, NR3R3, NR3COR3, NR3CO2R3, NR3CON(R3)2, NR3SO2R3, COR3, CO2R3, CON(R3)2, SO2N(R3)2, OCON(R3)2 said aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or C1-6 alkyl;
Y is selected from the group consisting of: S(O)p, xe2x80x94CH2xe2x80x94, CO, NR1, O, SO2NH, NHSO2;
Y2 is selected from the group consisting of: O, N(C1-15) alkyl, N(CO2)alkyl, Nxe2x80x94Oalkyl, Nxe2x80x94Oacyl and Nxe2x80x94OH, with the proviso that if Y2 is O and R3 is CH3 then n is 2;
Y1 is selected from the group consisting of: O, NH, S(O)p and C;
Z is selected from the group consisting of: CO2R3, R3CO2R3, CONHSO2Me, CONH2 and 5-(1H-tetrazole); or
(Zxe2x80x94W)t or (Zxe2x80x94W)v together with X1 can form a 5 or 6 membered ring, said ring being a carbocycle, aryl or heteroaryl and optionally substituted with 1 to 3 groups of Ra; in the case where (Zxe2x80x94W)t is used v is 0 or 1; in the case where (Zxe2x80x94W)v is used t is 0 or 1;
t and v are independently 0 or 1 such that t+v=1;
n is 2-4 and
p is 0-2.
Also included in the invention is a pharmaceutical composition which is comprised of a compound of formula I or Ia in combination with a pharmaceutically acceptable carrier.
Also included in the invention is a pharmaceutical composition which is comprised of a compound of formula I or Ia in combination with one or more known sulfonylureas, biguanides, xcex1-glucosidase inhibitors, other insulin secretogogues or insulin.
Also included in the invention is a method for raising high density lipoprotein (HDL) plasma levels in a mammal in need of such treatment comprising administering an effective amount of a compound of formula I or Ia.
Also included in the invention is a method for preventing, halting, slowing or otherwise treating the progression of atherosclerotic cardiovascular diseases and related conditions and disease events in a mammal in need of such treatment comprising administering an effective amount of a compound of formula I or Ia.
Also included in the invention is a method for preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events in a mammal in need of such treatment comprising administering an effective amount of a compound of formula I or Ia in combination with one or more active agents such as antihyperlipidemic agents, HMG-CoA synthase inhibitors, squalene epoxidase inhibitors and the like.
Also included in the invention is a method of treating or controlling diabetes and related diseases such as diabetic retinopathy, diabetic nephropathy and the like, which comprises administering to a mammalian diabetic patient an effective amount of a compound of formula I or Ia.
Also included in the invention is a method of treating or controlling diabetes and related diseases such as diabetic retinopathy; diabetic nephropathy and the like, which comprises administering a compound of formula I or Ia in combination with one or more known sulfonylureas, biguanides, xcex1-glucosidase inhibitors, other insulin secretogogues or insulin.
Also included in the present invention is a method of treating pancreatitis in a mammalian patient in need of such treatment, which is comprised of administering to said patient an amount of a compound of formula I or Ia which is effective for treating pancreatitis.
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term xe2x80x9calkylxe2x80x9d and the alkyl portion of xe2x80x9cacylxe2x80x9d refer to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
The carbon chain of xe2x80x9cacylxe2x80x9d also includes alkenyl and alkynyl groups as described below, with the double or triple bonds being located in appropriate positions within the chain.
Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following: 
wherein: x and y=from 0-10; and w and z=from 0-9.
The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.
When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
The term xe2x80x9calkenylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carbon-carbon double bonds may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
The term xe2x80x9calkynylxe2x80x9d refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
The term xe2x80x9calkoxyxe2x80x9d refers to those groups of the designated carbon length in either a straight or branched configuration attached through an oxygen linkage and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propargyloxy, and the like.
The term halo as used herein, represents fluoro, chloro, bromo or iodo.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like. Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted with 0-3 groups selected from Ra. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted as defined below. Preferred substituted aryls include phenyl and naphthyl substituted with zero or three groups of Ra.
Heteroaryl is a group containing from 5 to 10 atoms, 1-4 of which are heteroatoms, 0-4 of which heteroatoms are N and 0-1 of which are O or S, said heteroaryl group being unsubstituted or substituted with 0-3 Ra groups; examples of heteroaryls are pyridyl, quinolyl, purinyl, imidazolyl, imidazopyridyl and pyrimidinyl.
A subset of compounds of the invention is included herein and described in connection with formula I or Ia: 
as well as pharmaceutically acceptable salts thereof, wherein:
A represents a single or double bonded carbon, or a direct single or double bond;
Y represents a member selected from the group consisting of: xe2x80x94S(O)pxe2x80x94 wherein p is 0, 1 or 2, xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NR1xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94SO2NHxe2x80x94 and xe2x80x94NHSO2xe2x80x94;
one of t and v is zero and the other is 1;
W is 
xe2x80x83and
Z is selected from the group consisting of: CO2R3xe2x80x2, CONHSO2C1-6 alkyl, CONH2 and 5-(1H-tetrazolyl); or in the alternative,
one of (Zxe2x80x94W)t and (Zxe2x80x94W)v is taken in combination with X1 to represent a 5 or 6 membered fused ring, said ring being a carbocycle, aryl or heteroaryl ring, and being optionally substituted with 1 to 3 Ra groups;
when (Zxe2x80x94W)t is taken in combination with X1, v is 0 or 1, and when (Zxe2x80x94W)v is taken in combination with X1, t is 0 or 1;
X1 and X2 are independently selected from a group consisting of: H, OH, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, halo, C5-10 aryl, C5-10 heteroaryl, C1-10 acyl, C1-5 alkoxy, C5-10 aryloxy, C2-15 alkenyloxy, C2-15 alkynyloxy, heteroaryloxy, C1-10 acyloxy
said alkyl, alkenyl, alkynyl, aryl, acyl and heteroaryl, and the alkyl, alkenyl, alkynyl, aryl acyl and heteroaryl portions of alkoxy, aryloxy, alkenyloxy, alkynyloxy, heteroaryloxy and acyloxy being optionally substituted with 1 to 3 Ra groups;
n is 2, 3 or 4;
Y1 represents O, NH, CH2 or S(O)p wherein p is as defined above;
B represents a 5 or 6 membered fused ring containing 0 to 2 double bonds, and optionally containing 1 to 3 heteroatoms selected from the group consisting of O, S and N, said ring being optionally substituted with 1 to 3 Ra groups;
R1 is selected from a group consisting of: H, C1-15 alkyl, C2-15 alkenyl and C2-15 alkynyl, said alkyl, alkenyl and alkynyl being optionally substituted with 1 to 3 Ra groups;
R2 is selected from a group consisting of: H, OH, C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, C5-10 aryl, C5-10 heteroaryl, xe2x80x94C(O)C1-15 alkyl, CO2C1-6 alkyl, xe2x80x94OC(O)R3xe2x80x2, C1-6 alkoxy, C5-10 aryloxy, C2-15 alkenyloxy, C2-15 alkynyloxy, heteroaryloxy and C1-10 acyloxy,
said alkyl, alkenyl, alkynyl, aryl and heteroaryl, and the alkyl, aryl, alkenyl, alkynyl heteroaryl and acyl portions of alkoxy, aryloxy, alkenyloxy, alkynyloxy, heteroaryloxy and acyloxy being optionally substituted with 1 to 3 Ra groups;
R3 is selected from a group consisting of: H, OH, NHR1, NHacyl, C1-15 alkyl, C2-15 alkenyl, C1-15 alkoxy, CO2alkyl, C2-15 alkynyl, C5-10 aryl, and C5-10 heteroaryl said alkyl, alkenyl, alkynyl, aryl and heteroaryl optionally substituted with 1 to 3 Ra groups;
each Ra independently represents a member selected from the group consisting of: R3xe2x80x2, halo, CF3, OCF3, CN, NO2, OR3xe2x80x2, S(O)pxe2x80x94R3xe2x80x2; N(R3xe2x80x2)2, NR3xe2x80x2COR3xe2x80x2, NR3xe2x80x2CO2R3xe2x80x2, NR3xe2x80x2CON(R3xe2x80x2)2, NR3xe2x80x2SO2R3xe2x80x2, C(O)R3xe2x80x2, CO2R3xe2x80x2, CON(R3xe2x80x2)2, SO2N(R3xe2x80x2)2, OCON(R3xe2x80x2)2, and when R3xe2x80x2 is present and represents alkyl, alkenyl, alkynyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, aryl or heteroaryl group is optionally substituted with 1 to 3 halo, hydroxy, C1-3 alkoxy, carboxy or amino groups, and
when at least two Ra groups are present, they may also be taken in combination with any intervening atoms to represent a 4-6 membered ring, said ring containing 0-3 heteroatoms selected from O, S(O)p and N, and said ring being optionally interrupted by 1-2 xe2x80x94C(O)xe2x80x94 groups, and optionally substituted with 1-3 halo, hydroxy, C1-6 alkyl or amino groups;
R3xe2x80x2 represents H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl or heteroaryl;
R4 represents R2, xe2x80x94Dxe2x80x94R5 or 
D is selected from O, S(O)p, NR1 and CR6R7;
R5 is selected from the group consisting of: C5-10 aryl and C5-10 heteroaryl, said aryl and heteroaryl being optionally substituted with 1 to 3 Ra groups;
Y2 is selected from the group consisting of: O, N(C1-15) alkyl, N(CO2)alkyl, Nxe2x80x94Oalkyl, Nxe2x80x94Oacyl and Nxe2x80x94OH, with the proviso that if Y2 is O and R3 is CH3 then n is 2;
R8 is optional and is selected from the group consisting of CR6R7, O, NR6 and S(O)p,
and R6 and R7 are independently selected from H and C1-6 alkyl.
One embodiment of the invention which is particular interest is realized when Y is O and all other variables are as described above.
Another embodiment of the invention is realized when Y is S(O)p, p is 0-2 and all other variables are described as above.
Still another embodiment of the invention is realized when Y is xe2x80x94CH2xe2x80x94 and all other variables are described as above.
Yet another embodiment of the invention is realized when Y is CO and all other variables are described as above.
A further embodiment of the invention is realized when Y is NH and all other variables are described as above.
Another embodiment of the invention is realized when Y is NHSO2 or SO2NH and all other variables are described as above.
Another embodiment of the invention is realized when (Zxe2x80x94W)t or (Zxe2x80x94W)v together with X1 form a 5 or 6 membered ring, said ring being a carbocycle, aryl or heteroaryl and optionally substituted with 1 to 3 Ra groups. In the case where (Zxe2x80x94W)t is used, v is 0 or 1; in the case where (Zxe2x80x94W)v is used, t is 0 or 1; and all other variables are described as above.
Another embodiment of the novel compounds of the instant invention is realized when A is a single or double bonded carbon and all other variables are described as above.
Still another embodiment of the novel compounds of the instant invention is realized when A is a single or double bond and all other variables are described as above.
Still another embodiment of the invention is realized when B is a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1 to 3 heteroatoms selected from the group consisting of O, S and N, the heteroatom being present at any position in the five or six membered ring, the heterocycle being unsubstituted or substituted with 1 to 3 Ra groups, and all other variables are described as above.
Still another embodiment of the novel compounds of the instant invention is realized when R4 is selected from the group consisting of: R2, xe2x80x94Dxe2x80x94R5 and 
and all other variables are described as above. Preferably R4 represents R2 or xe2x80x94Dxe2x80x94R5.
A preferred embodiment of the invention is realized when:
R1 is H or C1-5 alkyl;
X1 and X2 are independently H or halo;
B is a 5 or 6 membered heterocycle containing 0 to 2 double bonds, and 1 to 3 heteroatoms selected from the group consisting of O, S and N, the heteroatom being at any allowable position in the five or six membered heterocycle, the heterocycle being unsubstituted or substituted with 1 to 3 Ra groups;
Y is O, NH or S;
Y1 is O;
W is xe2x80x94CR6R7xe2x80x94;
Ra is a member selected from the group consisting of: halo, aryl, heteroaryl, CF3, OCF3, xe2x80x94Oxe2x80x94, CN, NO2, R3xe2x80x2, OR3xe2x80x2; SR3xe2x80x2, S(O)R3xe2x80x2, SO2R3xe2x80x2, NR3xe2x80x2COR3xe2x80x2, COR3xe2x80x2, CON(R3xe2x80x2)2, SO2N(R3xe2x80x2)2, said aryl and heteroaryl optionally substituted with 1 to 3 halo or C1-6 alkyl groups; and
Z is CO2R3xe2x80x2, CONHSO2Me, CONH2 or 5-(1H-tetrazolyl). All other variables are as originally defined.
Another preferred embodiment of the invention is realized when:
R1 is H or C1-5 alkyl;
R4 is R2, xe2x80x94Dxe2x80x94R5 or 
X1 and X2 are independently H or halo;
Y is O, NH or S;
Y1 is O;
W is xe2x80x94CR6R7xe2x80x94;
Ra is a member selected from the group consisting of: halo, aryl, heteroaryl, CF3, OCF3, xe2x80x94Oxe2x80x94, CN, NO2, R3xe2x80x2, OR3xe2x80x2; SR3xe2x80x2, S(O)R3xe2x80x2, SO2R3xe2x80x2, NR3xe2x80x2COR3xe2x80x2, COR3xe2x80x2, CON(R3xe2x80x2)2, SO2N(R3xe2x80x2)2, wherein R3xe2x80x2 represents H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl or heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 groups of halo or C1-6 alkyl; and
Z is CO2R3xe2x80x2, CONHSO2Me, CONH2 or 5-(1H-tetrazolyl).
Still another preferred embodiment of the invention is realized when:
R1 is C1-15 alkyl;
R4 is xe2x80x94Dxe2x80x94R5 or 
X2 is H, or halo;
Y is O, NH or S;
Y1 is O;
Ra is a member selected from the group consisting of: halo, aryl, heteroaryl, CF3, OCF3, xe2x80x94Oxe2x80x94, CN, NO2, R3xe2x80x2, OR3xe2x80x2; SR3xe2x80x2, S(O)R3xe2x80x2, SO2R3xe2x80x2, NR3xe2x80x2COR3xe2x80x2, COR3xe2x80x2, CON(R3xe2x80x2)2, SO2N(R3xe2x80x2)2, said aryl and heteroaryl optionally substituted with 1 to 3 halo or C1-6 alkyl groups;
R3xe2x80x2 represents H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl or heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 3 halo or C1-6 alkyl groups;
(Zxe2x80x94W)t or (Zxe2x80x94W)v together with X1 forms a 5 or 6 membered ring, said ring being a carbocycle, aryl or heteroaryl and optionally substituted with 1 to 3 Ra groups; in the case where (Zxe2x80x94W)t is used v is 0 or 1; in the case where (Zxe2x80x94W)v is used t is 0 or 1; and all other variables are described as above.
Examples of compounds of the invention include the following:
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-acetic acid;
2-(2-(3-(2,2-Dimethylpropyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-(2,2-dimethyl)acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indole-5-propan-3-oic acid;
2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indole-5-propan-3-oic acid;
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-oxyacetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-5-oxyacetic acid;
N-[2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indol-5-yl]glycine;
N-[2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-indol-5-yl]glycine;
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-6-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-indole-6-acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-4-chloroindole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-4-chloroindole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-quinolin-6-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-quinolin-6-acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinolin-7-acetic acid;
2-(2-(3-Neopentyl7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinolin-7-acetic acid;
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-quinazolin-6-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-quinazolin-6-acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinazolin-7-acetic acid;
2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-quinazolin-7-acetic acid;
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-3-methylindole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-3-methylindole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-3-butylindole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-3-butylindole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)-7-propylindole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)-7-propylindole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-N-methylindole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)-N-methylindole-5-acetic acid;
2-(3-(3-Phenyl-7-propylbenzofuran-6-yloxy)propy)indole-5-acetic acid;
2-(3-(3-Neopentyl-7-propylbenzofuran-6-yloxy)propy)indole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenz[4,5]isoxazol-6-yloxy)propyl)indole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenz[4,5]isoxazol-6-yloxy)propyl)indole-5-acetic acid;
2-(2-(3-Phenyl-7-(cyclopropylmethyl)benzofuran-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-Neopentyl-7-(cyclopropylmethyl)benzofuran-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)indole-5-acetic acid;
2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)benzofuran-5-acetic acid;
2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)indole-5-oxyacetic acid;
2-(2-(1-Phenyl-4-propylindol-5-yloxy)ethyl)indole-5-propan-3-oic acid;
2-(2-(4-Phenoxy-3-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-(4-Tolyloxy)-3-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-Valeryl-3-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-Benzoyl-3-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-(N-Hydroxyimino)valeryl-3-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-(N-Hydroxyimino)benzoyl-3-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(3-(3-Fluorophenyl)-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-(Phen-2-ethyl)-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-(4-t-Butylphenyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-(2,2-Dimethyl-2-phenylethyl)-7-propylbenz[4,5]isoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid sodium salt;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid methyl ester;
2-(2-(3-(2-Phenyl)ethyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-Phenyl-7-(n-propyl)benzofuran-6-yloxy)ethyl)-benzofuran-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylic acid sodium salt;
2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylic acid; and
2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylic acid.
Preferred examples of the compounds of the invention are as follows:
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzisoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenzofuran-6-yloxy)ethyl)benzothiophen-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzofuran-6-yloxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-Phenyl-7-propylbenzisoxazol-6-yloxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-Neopentyl-7-propylbenzisoxazol-6-yloxy)ethyl)benzothiophen-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid methyl ester;
2-(2-(3-(2-Phenyl)ethyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)indole-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)benzofuran-5-acetic acid;
2-(2-(3-Phenyl-7-(n-propyl)benzofuran-6-yloxy)ethyl)-benzofuran-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylic acid sodium salt;
2-(2-(3-Phenyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylic acid; and
2-(2-(3-(2,2-Dimethylpropyl)-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylic acid.
More preferred compounds are as follows:
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid;
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid methyl ester;
2-(2-(3-(2-Phenyl)ethyl-7-(n-propyl)benz[4,5]isoxazol-6-yloxy)ethyl)indole-5-acetic acid and
2-(2-(4-Phenoxy-2-propylphenoxy)ethyl-6,7,8,9-tetrahydronaphtho[2,1-b]furan-7-carboxylic acid sodium salt.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
Compounds of the general Formula I or Ia may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
Alternatively, any enantiomer of a compound of the general Formula I or Ia may be obtained by stereospecific synthesis using optically pure starting materials of known configuration.
The instant compounds can be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic and the like. In addition, certain compounds containing an acidic function such as a carboxy or tetrazole, can be isolated in the form of their inorganic salt in which the counterion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
As previously indicated, the compounds of the present invention have valuable pharmacological properties. They are useful in treating or preventing diabetes and related diseases such as diabetic retinopathy, diabetic nephropathy and the like, treating obesity, lowering triglyceride levels and preventing vascular restenosis, and treating pancreatitis. They are useful in treating other disorders where insulin resistance is a component including ovarian hyperandrogenism (polycyctic ovarian syndrome). They are also useful in raising high density lipoprotein levels, preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events.
The present invention further provides a compound of the general Formula I or Ia, or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of hyperglycemia (diabetes) in human or non-human animals.
The present invention further provides a compound of the general Formula I or Ia, or a pharmaceutically acceptable salt or ester thereof, in combination with sulfonylureas, biguanides, xcex1 glucosidase inhibitors, other insulin secretogogue or insulin for use in the treatment of diabetes and related diseases such as diabetic retinopathy; diabetic nephropathy and the like; pancreatitis; obesity, lowering triglyceride levels, vascular restenosis, other disorders where insulin resistance is a component, such as ovarian hyperandrogenism (polycyctic ovarian syndrome), raising high density lipoprotein levels, and preventing, halting or slowing the progression of atherosclerotic cardiovascular diseases and related conditions and disease events and hypertension in human or non-human animals.
In one aspect, the present invention provides a compound of Formula I or Ia for use in the treatment of obesity in human or non-human animals. Said compound can be effectively used in combination with other known or proposed strategies for the treatment of obesity or obesity-related disorders; for example, fenfluramine, dexfenfluramine, phentermine and xcex23 adrenergic receptor agonist agents.
Diabetes mellitus is characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies. The instant compounds can be effectively used alone as well as in combination with known therapies for diabetes including insulin, sulfonylureas, biguanides (such as metformin), xcex1-glucosidase inhibitors (such as acarbose) and others.
Two major forms of diabetes mellitus are now recognized. Type I diabetes, or insulin-dependent diabetes, is the result of a deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or non-insulin dependent diabetes, often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissue to respond appropriately to insulin. Most Type II diabetics are also obese. Accordingly, an aspect the present invention provides a method of lowering triglyceride levels which comprises administering, to a mammal in need thereof, a therapeutically effective amount of a compound of the formula I or Ia or pharmaceutically acceptable salt or ester thereof.
In addition the compounds of the present invention lower or modulate triglyceride levels and/or cholesterol levels and raise HDL plasma levels and are therefore of use in treating medical conditions wherein such lowering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hypertension, obesity, atherosclerotic disease events, diabetes and related conditions by administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula I or Ia or a pharmaceutically acceptable salt thereof.
The compositions are comprised of a compound of formula I or Ia in combination with a carrier. They may also contain other active ingredients known for use in the treatment of atherosclerotic disease events, diabetes, hypertension, obesity and related conditions, for example, fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis, such as HMG-CoA reductase inhibitors, for example, lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption, for example, beta-sitosterol, and (acyl CoA:cholesterol acyltransferase) inhibitors, for example, melinamide; anion exchange resins, for example, cholestyramine, colestipol or a dialkylaminoalkyl derivatives of a cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics.
In particular the invention provides methods for preventing or reducing the risk of developing atherosclerosis, comprising the administration of a prophylactically effective amount of a compound of formula I or Ia alone or in combination with one or more additional pharmaceutically active agents, to a mammal, particularly human, who is at risk of developing atherosclerosis.
Atherosclerosis as used herein encompasses vascular diseases and conditions that are recognized and understood by practicing physicians. Atherosclerotic cardiovascular disease, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vessel disease are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms xe2x80x9catherosclerosisxe2x80x9d and xe2x80x9catherosclerotic disease.xe2x80x9d
The instant invention further provides methods for preventing or reducing the risk of a first or subsequent (where the potential exists for recurrence) atherosclerotic disease event, comprising the administration of a prophylactically effective amount, or more particularly, an anti-atherosclerotic effective amount of cholesterol biosynthesis inhibitor, of a compound of formula I or Ia alone or in combination with one or more additional pharmaceutically active agents, to a mammal, particularly human, who is at risk for having an atherosclerotic disease event. The term xe2x80x9catherosclerotic disease eventxe2x80x9d as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease event are those for whom the potential for recurrence of such an event exists.
Persons to be treated with the instant therapy include those at risk of developing atherosclerotic disease and of having an atherosclerotic disease event. Standard atherosclerotic disease risk factors are known to the average physician practicing in the relevant fields of medicine. Such known risk factors include but are not limited to hypertension, smoking, diabetes, low levels of high density lipoprotein cholesterol, high levels of low density lipoprotein cholesterol, and a family history of atherosclerotic cardiovascular disease. Published guidelines for determining those who are at risk of developing atherosclerotic disease can be found in: National Cholesterol Education Program, Second report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), National Institute of Health, National Heart Lung and Blood Institute, NIH Publication No. 93-3095, September 1993; abbreviated version: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Summary of the second report of the national cholesterol education program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), JAMA, 1993, 269, pp. 3015-23. People identified as having one or more of the above-noted risk factors, as well as people who already have atherosclerosis, are intended to be included within the group of people considered to be at risk for having an atherosclerotic disease event.
The compounds of the present invention may be orally administered as a pharmaceutical composition, for example, with an inert diluent, or with an edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or incorporated directly into food. For oral therapeutic administration, which includes sublingual administration, these active compounds may be incorporated with excipients and used in the form of tablets, capsules, ampules, sachets, elixirs, suspensions, syrups and the like. Such compositions and preparations may contain, e.g., at least about 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 90 percent of the weight of the unit. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition.
When treating or preventing diabetes mellitus and/or hyperglycemia or hypertriglyceridemia, or obesity, or when treating, preventing or slowing the progression of atherosclerosis, generally satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.1 milligram to about 100 milligrams per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
The compounds of the instant invention may be used effectively alone or in combination with one or more additional active agents depending on the desired target therapy. Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of formula I or Ia and one or more additional active agents, as well as administration of a compound of formula I or Ia and each active agent in its own separate pharmaceutical dosage formulation. For example, a compound of formula I or Ia and an HMG-CoA reductase inhibitor can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where separate dosage formulations are used, a compound of formual I or Ia and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at staggered times, i.e, sequentially. Combination therapy is understood to include all these regimens.
An example of combination treatment or prevention of atherosclerosis may be wherein a compound of formula I or Ia is administered in combination with one or more of the following active agents: an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent such as a cholesterol biosynthesis inhibitor, for example an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, or a squalene synthetase inhibitor (also known as squalene synthase inhibitor); an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor such as melinamide; probucol; nicotinic acid and the salts thereof and niacinamide; a cholesterol absorption inhibitor such as beta-sitosterol; a bile acid sequestrant anion exchange resin such as cholestyramine, colestipol or dialkylaminoalkyl derivatives of a cross-linked dextran; an LDL (low density lipoprotein) receptor inducer; fibrates such as clofibrate, bezafibrate, fenofibrate, and gemfibrizol; vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCl salt; vitamin B12 (also known as cyanocobalamin); anti-oxidant vitamins such as vitamin C and E and beta carotene; a beta-blocker; an angiotensin II antagonist; an angiotensin converting enzyme inhibitor; and a platelet aggregation inhibitor such as fibrinogen receptor antagonists (i.e., glycoprotein IIb/IIIa fibrinogen receptor antagonists) and aspirin. As noted above, the compounds of formula I or Ia can be administered in combination with more than one additional active agent, for example, a combination of a compound of formula I or Ia with an HMG-CoA reductase inhibitor (e.g. lovastatin, simvastatin and pravastatin) and aspirin, or a compound of formula I or Ia with an HMG-CoA reductase inhibitor and a beta adrenergic blocking drug.
Another example of combination therapy can be seen in treating obesity or obesity-related disorders, wherein the compounds of formula I or Ia may be effectively used in combination with for example, fenfluramine, dexfenfluramine, phentermine and xcex23 adrenergic receptor agonist agents.
Still another example of combination therapy can be seen in treating diabetes and related disorders wherein the compounds of formula I or Ia can be effectively used in combination with for example sulfonylureas, biguanides, xcex1-glucosidase inhibitors, other insulin secretogogues, insulin as well as the active agents discussed above for treating atherosclerosis.
In accordance with this invention, a pharmaceutically effective amount of a compound of formula I or Ia can be used for the preparation of a medicament useful for treating diabetes, treating obesity, lowering tryglyeride levels, raising the plasma level of high density lipoprotein, and for treating, preventing or reducing the risk of developing atherosclerosis, and for preventing or reducing the risk of having a first or subsequent atherosclerotic disease event in mammals, particularly in humans.
Additionally, an effective amount of a compound of formula I or Ia and a therapeutically effective amount of one or more active agents selected from the group consisting of: an antihyperlipidemic agent; a plasma HDL-raising agent; an antihypercholesterolemic agent such as a cholesterol biosynthesis inhibitor, for example an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, a squalene epoxidase inhibitor, or a squalene synthetase inhibitor (also known as squalene synthase inhibitor); an acyl-coenzyme A: cholesterol acyltransferase inhibitor; probucol; nicotinic acid and the salts thereof; niacinamide; a cholesterol absorption inhibitor; a bile acid sequestrant anion exchange resin; a low density lipoprotein receptor inducer; clofibrate, fenofibrate, and gemfibrozol; vitamin B6 and the pharmaceutically acceptable salts thereof; vitamin B12; an anti-oxidant vitamin; a beta-blocker; an angiotensin II antagonist; an angiotensin converting enzyme inhibitor; a platelet aggregation inhibitor; a fibrinogen receptor antagonist; aspirin; fenfluramine, dexfenfluramine, phentermine, xcex23 adrenergic receptor agonists; sulfonylureas, biguanides, xcex1-glucosidase inhibitors, other insulin secretogogues and insulin can be used together for the preparation of a medicament useful for the above-described treatments.
The tablets, capsules and the like may also contain a binder such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit is in the form of a capsule, it may also contain a liquid carrier, such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
The compounds of the present invention may also be administered parenterally, i.e, intramuscularly, intravenously, transdermally or subcutaneously. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Specific examples of formula I or Ia may require the use of protecting groups to enable their successful elaboration into the desired structure. Protecting groups may be chosen with reference to Greene, T. W., et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1991. The blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenation.
Non-limiting examples of suitable hydroxyl protecting groups are: trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, and allyloxycarbonyl. Non-limiting examples of suitable carboxyl protecting groups are benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl.
The process for making the compounds of the instant invention is generally depicted in Scheme 1 and 2 below: 
The invention is further illustrated in connection with the following non-limiting examples.